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Aleo, S.J.* ; Del Dotto, V.* ; Romagnoli, M.* ; Fiorini, C.* ; Capirossi, G.* ; Peron, C.* ; Maresca, A.* ; Caporali, L.* ; Capristo, M.* ; Tropeano, C.V.* ; Zanna, C.* ; Ross-Cisneros, F.N.* ; Sadun, A.A.* ; Pignataro, M.G.* ; Giordano, C.* ; Fasano, C.* ; Cavaliere, A.* ; Porcelli, A.M.* ; Tioli, G.* ; Musiani, F.* ; Catania, A.* ; Lamperti, C.* ; Marzoli, S.B.* ; De Negri, A.* ; Cascavilla, M.L.* ; Battista, M.* ; Barboni, P.* ; Carbonelli, M.* ; Amore, G.* ; La Morgia, C.* ; Smirnov, D. ; Vasilescu, C. ; Farzeen, A. ; Blickhaeuser, B. ; Prokisch, H. ; Priglinger, C.* ; Livonius, B.* ; Catarino, C.B.* ; Klopstock, T.* ; Tiranti, V.* ; Carelli, V.* ; Ghelli, A.M.*

Genetic variants affecting NQO1 protein levels impact the efficacy of idebenone treatment in Leber hereditary optic neuropathy.

Cell Rep. Med. 5:101383 (2024)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Idebenone, the only approved treatment for Leber hereditary optic neuropathy (LHON), promotes recovery of visual function in up to 50% of patients, but we can neither predict nor understand the non-responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons to respiratory complex III, bypassing complex I affected in LHON. We show here that two polymorphic variants drastically reduce NQO1 protein levels when homozygous or compound heterozygous. This hampers idebenone reduction. In its oxidized form, idebenone inhibits complex I, decreasing respiratory function in cells. By retrospectively analyzing a large cohort of idebenone-treated LHON patients, classified by their response to therapy, we show that patients with homozygous or compound heterozygous NQO1 variants have the poorest therapy response, particularly if carrying the m.3460G>A/MT-ND1 LHON mutation. These results suggest consideration of patient NQO1 genotype and mitochondrial DNA mutation in the context of idebenone therapy.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Lhon ; Leber Hereditary Optic Neuropathy ; Nqo1 ; Complex I ; Cybrids ; Fibroblasts ; Idebenone ; Mtdna ; Retinal Ganglion Cells; Mtdna; Cells; Mitochondria; Progression; Antioxidant; Apoptosis; Accuracy; Analogs; Epi-743; Chain
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 2666-3791
e-ISSN 2666-3791
Zeitschrift Cell Reports Medicine
Quellenangaben Band: 5, Heft: 2, Seiten: , Artikelnummer: 101383 Supplement: ,
Verlag Cell Press
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503292-001
Förderungen European Commission
Associazione Luigi Comini, Onlus
Italian Ministry of Health
German Federal Ministry of Education and Research (BMBF
Bonn, Germany)
E-Rare project GENOMIT
Center for the Study of Mitochondrial Pediatric Diseases - Mariani Foun-dation
DOI 10.1016/j.xcrm.2023.101383
WOS ID 001202186400001
Scopus ID 85182989562
PubMed ID 38272025
Erfassungsdatum 2024-01-29
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